Acyloxy-2-aryl-1, 3-thiazinones



United States Patent 3,336,305 ACYLOXY-2-ARYL-1,3-THIAZINONES Homer C. Scarborough, deceased, late of Evansville, Ind., by Phyllis Jean Scarborough, legal representative, Evansville, Ind., and Charles Albert Hanning, Chandler, Ind., assignors to Mead Johnson & Company, Evansville, Ind., a corporation of Indiana No Drawing. Filed Dec. 9, 1964, Ser. No. 417,246 5 Claims. (Cl. 260-243) This invention relates to novel chemical compounds having pharmaceutical utility, with the preparation of these substances and with their pharmaceutical use.

In accordance with the present invention it has been found that certain acyloxy-Z-aryl-1,3-thiazinones have effective uricosuric activity. The compounds of the invention, for purposes of description, can be represented by general Formula I:

I 3,336,305 Patented Aug. 15, 1967 wherein X and Y have the same meaning as above, with at least one chemical equivalent of a carboxylic acid anhydride having the formula wherein R has the same meaning as above. This process is preferably carried out by contacting the two reactants with one another in solution at a temperature from about 50 C. to about 170 C. It is preferable to use as reaction solvent an excess of the carboxylic acid anhydride. By excess is meant more than one molecular proportion thereof relative to the thiazinedione reactant. In practice, 10 to 15 milliliters of anhydride per gram of thiazinedione has proved convenient. The reaction is permitted to continue for a sufiicient period, generally from 1 to 5 hours, to effect appreciable formation of the desired reaction product which can be removed in solid form by suitable means.

The following examples are provided to illustrate in detail several specific embodiments of the invention. They are not intended, however, to limit the scope of the invention.

EXAMPLE I TABLE I.EXAMPLES l'I-XIII O Y B I Y l S 0 S (R; 0 Heatin 4 2 e X 0 A Analysis Ex- A and B selected Molecular Yield, ample from O: and X Y M.P. Formula Percent Calcd Found C H N C H N II CHM l F-O H H l 93. 5-5. 5 CuHaNOaS 67 58.29 3. 67 5. 67 58. 41 4.02 5.51

0 III CHaii-O 4-01 B 130-2. 5 CnHaClNOsS 10 51. 17 2.86 4.97 51.23 3. 12 4.90

n IV CHaCHzC-O 4-Cl H I 91.5-4 CnHmClNOzqS 62 52.79 3. 41 4. 74 52. 78 3.70

V CH i-O 4-OCH; H b 131. 5-5.5 CnHnNO4S 73 56. 31 4. 00 5.05 56. 16 4.30 5. 04

VI CHaCHz-O 400E; H B 111. 5-3.5 CuHnNOeS 67 57.72 4.50 4.81 57.68 4. 83 4.69

(H) VII CHaCO 4-NO, H b 182-4 CnHsNzOsS 78 49. 31 2.76 9. 59 49.45 2.97 9. 42

See footnotes at end of table.

TABLE "1-Continued Analysis Ex- A and B selected Molecular Yield, ample from and X Y MP. Formula Percent Calcd Found C H N C H N VI 11.... CH CHziL-O it-NO; H b 142. 5-5.5 CnHroNrOsS 50 50.97 3. 29 9. 15 51. 3. 64 9. 19

I X CHA-O 4-CH; H d 132-4 CnHjiNOsS 75 59. 75 4.25 5. 39 50.46 4.15 5.16

X CH3CH2( J-O -CH; H 79-81 C14H13N03S 65 61.07 4. 76 5. 09 61. 04 4.92 4.91.

i XI CHaCHzCHzO-O 4-CH3 H l 60. 5-63 CisHrsNOaS 42 02. 26 5. 22 4. 84 61.98 5. 32 4. 64

XII..." CHaCHriL-O 3-N0r H a 88. 5-90 ClaHroNzOsS 67 50.97 3.29 9. 50. 73 3.38 0.10

XIII CHaCHzC-O 3-01 4-01 h 88. 5-90 O 3HC1zNOaS 77 47. 29 3 21. 48 2.75 47. 29 3 21. 57 2. 69

1 Corrected melting points, C. Heptane, b Aoetonitrlle, a Isopropyl Acetate, Ethyl Acetate, MeOH. 2 Compound III was obtained by reacting 4-ehlorothioacetamide with malonie acid in acetic anhydride; yield calculation based on the thloamide 3 Chlorine analysis.

One reliable index of uricosuric activity is the ability of the test compound to induce retention of phenol red in the circulatory system of a rat. The compounds embraced by the present invention were tested for this ability. In these tests, adult albino rats of either sex were pretreated with the test compound orally 15 minutes before being anesthetized with dial-urethane (0.5 milliliter per kilogram, intraperitoneally). Fifteen minutes later each rat received via the caudal vein 75 milligrams of phenol red per kilogram as a 1.5% solution in 0.9% sodium chloride. Then, 30 and 60 minutes after dye injection blood samples were taken from the retro-orbital plexus into heparinized capillary tubes which were then centrifuged. The amount of phenol red remaining in plasma was determined by transferring, via Sahli pipettes, 0.02 milliliter aliquots of plasma into 12 x 75 millimeter Coleman cuvettes containing 1.5 milliliters of 0.1 N sodium hydroxide and read against blanks containing plasma, saline, and 0.05 milliliter of 0.1 N hydrochloric acid at 540 nm on the Coleman Jr. spectrophotometer. Micrograms of phenol red remaining per milliliter of plasma were calculated from optical density reading and a previously determined standard curve.

TABLE II Oral MRD 1 Product of: mg./ kg. Example II 12.5 Example I-Lot 1 6.3 Example III 50 Example IV Example V 100 Example IX 100 Example X 100 1 MRDzminimal retentive dose; lowest mg./kg. dose tested which produced significant retention of phenol red in plasma of rats receiving test compound orally minutes prior to dye injection. For purposes of comparison one of the best known uricosuric agents which is presently in clinical use exhibits MRD (minimal retentive dose) values in the phenol red retention test of 125-25 milligrams per kilogram.

The uricosuric agents of the invention can be administered orally to humans in the treatment or prevention of gout to increase uric acid secretion. For this purpose dosages from about 50-100 milligrams per day can be employed. Dosage unit forms of the active uricosuric agent such as capsules, powders, tablets and liquids containing from 25 to 100 milligrams of the active agents are convenient for administration in dosages in this range.

As used herein the formula A is a generic formula which embraces compounds of the following formulae:

1? Y B Y s s c 43 c i N X N X A A wherein A, B, X and Y are as previously indicated.

Those modifications and equivalents which fall within the spirit of the invention and the scope of the appended claims are to be considered part of the invention.

We claim:

1. An acyloxy-2-phenyldihydro-1,3-thiazinone having the formula A and B are different and are selected from O and 0 R("30- R is an alkyl group of from 1 to 4 carbon atoms, and X and Y are selected from hydrogen, halogen, nitro, alkoxy of up to 4 carbon atoms, and alkyl of up to 4 carbon atoms. 2. A compound in accordance with claim 1 wherein R iS C2H5.

3. A compound in accordance with claim 1 wherein R is CH 4. A compound in accordance with claim 1 wherein R is C H and X and-Y are hydrogen.

5. A compound in accordance with claim 1 wherein R is CH and X and Y are hydrogen.

References Cited Fieser et al., Advanced Organic Chemistry, Reinhold Pub. Corp., New York (1961), pages 450 and 289.

.WALTER A. MODANCE, Primary Examiner.

J. M. FORD, Assistant Examiner. 

1. AN ACYLOXY-2-PHENYLDIHYDRO-1,3-THIAZINONE HAVING THE FORMULA 